This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Cellular tissue is continually subjected to damaging agents such as sunlight and chemical pollutants externally, and oxidation and hydrolysis internally (Prakash et al., 2005). A variety of DNA repair pathways have evolved to repair the resulting lesions, but some lesions escape repair and will be encountered by the replication machinery. The newly discovered translesion DNA synthesis (TLS) polymerases allow cells to cope with unrepaired DNA damage by promoting replication through lesions that would otherwise stall the replication fork. Humans have four such TLS polymerases [unreadable]Pol[unreadable], Pol[unreadable], Pol[unreadable], and Rev1 [unreadable]each with a unique DNA damage bypass and fidelity profile. Pol[unreadable], for example, is unique in its proficient ability to replicate through a UV-induced cis-syn cyclobutane thymine-thymine (T-T) dimer) by inserting two adenines opposite the dimer. Mutations in human Pol[unreadable] are responsible for an inherited cancer-prone disorder, the variant form of xeroderma pigmentosum (XP-V). Pol[unreadable] is, thus, the first DNA polymerase demonstrated to act as a tumor suppressor. Pol[unreadable], on the other hand, is specialized in the extension of mispaired primer termini on undamaged DNAs, and in the extension step of lesion bypass. To understand how these polymerases exchange with "classical" polymerases, we have also initiated studies on the lagging/leading strand polymerases [unreadable] and [unreadable] in eukaryotes.